Oral mucosa is uniquely known for its scarless and expedited wound healing compared to skin. Nonetheless, lines of evidence accumulate at the alarming rate that certain drugs used to treat bone- associated diseases specifically induce osteonecrosis of the jaw (ONJ) and delay wound healing of oral mucosa, leading to considerable clinical complications and compromising the patients' quality of life. The long- term users of these drugs, bisphosphonates (BP) and denosumab, are at the higher risk of developing ONJ, clinically defined as exposed necrotic bone with unhealed overlaying oral mucosa for at least 8 weeks. Both drugs have the common mechanisms of actions; they inhibit functions of osteoclasts, bone resorbing cells that are critically important for bone remodeling. However, the exact mechanisms as to why and how these bone- related drugs compromise the healing of the overlaying oral mucosal tissues are largely unknown. The lack of fundamental understanding in drug-induced ONJ is presumably due to the missing gaps in knowledge about osteomucosal healing, a combinatorial healing process of the soft and hard tissues as one entity that uniquely occurs in the oral cavity. To address this issue, we performed the high-throughput microarray analysis using the BRONJ mouse model at the sites of osteomucosal wounds and found series of differentially expressed genes including secretory proteins. We further developed a mouse model for DRONJ and found similar ONJ-like lesions. Based on our preliminary studies, we hypothesize that the osteomucosal wound healing is orchestrated by cross interactions among cells in soft and hard tissues via secretory proteins at the site of wound, and that drug-induced ONJ is developed by deregulating such interactions by BP and denosumab, leading to distinct molecular alterations and impaired osteomucosal healing. The objectives of this proposal are: 1) to investigate role of RANKL, a secretory protein important for bone remodeling and healing, using genetically engineered mice; 2) to identify genes/proteins that are commonly deregulated in BRONJ- and DRONJ-like lesions using the high-throughput microarray and proteomics; and 3) to investigate the cross interactions between different cell types using co-culture systems as well as our newly developed osteomucosal tissue constructs in vitro. Oral mucosal tissues are anatomically situated in close proximity to the underlying bone tissues, suggesting that the drug-induced ONJ in the oral cavity may be associated with the impaired cross-talks between these two entities during the osteomucosal wound healing processes. Current proposal would help unraveling the molecular mechanisms of rather unexplored areas of research in osteomucosal wound healing and provide knowledge for future therapeutic applications to both BRONJ and DRONJ.